The present invention relates to novel substituted carbonic acid esters and urethanes, processes for their preparation, and the use thereof.
Numerous blocking groups are known for use in the reaction of primary and secondary amines, especially amino acids, biogenic amines, and amino sugars. A more recent compilatory disclosure is found, for example, in the two books by W. Wunsch and E. Muller (Editor), Houben-Weyl, "Methoden der Organischen Chemie" (Methods of Organic Chemistry), 15/1, Georg Thieme publishers, Stuttgart, 1974, and H. D. Jakubke and H. Jeschkeit, "Aminosauren-Peptide-Proteine" (Amino Acids-Peptides-Proteins), 2nd Edition, Adademie Publishers, Berlin 1973.
Although the conventional amino blocking groups of the urethane type (Boc, Z) accomplished many of the requirements of unequivocally progressing structural synthesis principles, it is desirable in many instances to employ blocking groups which can be split off under very gentle acidolytic conditions. This permits an optimally gentle treatment of acid-labile blocking groups, for example, on trifunctional amino acids, and especially, for instance, in syntheses with repetitive coupling and unblocking steps (solid-phase or liquid-phase techniques). Also, tryptophancontaining peptides, for example, frequently experience a destruction of the indole system during deacylations in a more strongly acidic medium, manifesting itself in a violet discoloration and a shift in UV absorption. Secondary reactions of this type can be reduced to a minimum when using gentle unblocking reagents.
The following abbreviations are used throughout this application for convenience: Boc=tert-butoxycarbonyl; Bzl=benzyl; Z=benzyloxycarbonyl; DCC=dicyclohexylcarbodiimide; DCHA=dicyclohexylamine; DMF=dimethylformamide; HOBt=1-hydroxybenzotriazole; HoSu=N-hydroxysuccinimide; Ph=phenyl; "Triton B"=trimethylbenzylammonium hydroxide.
The recently developed blocking groups Bpoc, Ddz, Ppoc, Azoc (abbreviations in accordance with the general rules of peptide chemistry, cf. Houben-Weyl, "Methoden der Organischen Chemie," 15/1, Georg Thieme publishers, Stuttgart, 1974 and H. D. Jakubke and H. Jeschkeit, "Aminosauren-Peptide-Proteine," 2nd Edition, Akademie publishers, Berlin, 1973), meet these requirements, but only the first two compounds are suitable for more widespread use. In both cases, the storage of the blocked amino acids is not entirely without problems for reasons of autocatalytical decomposition and/or photoability. Also the Bpoc phenyl carbonate, frequently employed for introducing the Bpoc group, tends to decompose even at low temperatures. The production of Bpoc-Trp-OH is accomplished only with very low yields.